星空体育频道: 2013-08-18

2013年8月24日星期六

Unprecedented control of genome editing in flies promises insight into human development, disease

Aug. 23, 2013 — In an era of widespread genetic sequencing, the ability to edit and alter an organism's DNA is a powerful way to explore the information within and how it guides biological function.

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A paper from the University of Wisconsin-Madison in the August issue of the journal Genetics takes genome editing to a new level in fruit flies, demonstrating a remarkable level of fine control and, importantly, the transmission of those engineered genetic changes across generations.

Both features are key for driving the utility and spread of an approach that promises to give researchers new insights into the basic workings of biological systems, including embryonic development, nervous system function, and the understanding of human disease.

"Genome engineering allows you to change gene function in a very targeted way, so you can probe function at a level of detail" that wasn't previously possible, says Melissa Harrison, an assistant professor of biomolecular chemistry in the UW-Madison School of Medicine and Public Health and one of the three senior authors of the new study.

Disrupting individual genes has long been used as a way to study their roles in biological function and disease. The new approach, based on molecules that drive a type of bacterial immune response, provides a technical advance that allows scientists to readily engineer genetic sequences in very detailed ways, including adding or removing short bits of DNA in chosen locations, introducing specific mutations, adding trackable tags, or changing the sequences that regulate when or where a gene is active.

The approach used in the new study, called the CRISPR RNA/Cas9 system, has developed unusually fast. First reported just one year ago by scientists at the Howard Hughes Medical Institute and University of California, Berkeley, it has already been applied to most traditional biological model systems, including yeast, zebrafish, mice, the nematode C. elegans, and human cells. The Wisconsin paper was the first to describe it in fruit flies and to show that the resulting genetic changes could be passed from one generation to the next.

"There was a need in the community to have a technique that you could use to generate targeted mutations," says Jill Wildonger, a UW-Madison assistant professor of biochemistry and another senior author of the paper. "The need was there and this was the technical advance that everyone had been waiting for."

"The reason this has progressed so quickly is that many researchers -- us included -- were working on other, more complicated, approaches to do exactly the same thing when this came out," adds genetics assistant professor Kate O'Connor-Giles, the third senior author. "This is invaluable for anyone wanting to study gene function in any organism and it is also likely to be transferable to the clinical realm and gene therapy."

The CRISPR RNA/Cas9 system directs a DNA-clipping enzyme called Cas9 to snip the DNA at a targeted sequence. This cut then stimulates the cell's existing DNA repair machinery to fill in the break while integrating the desired genetic tweaks. The process can be tailored to edit down to the level of a single base pair -- the rough equivalent of changing a single letter in a document with a word processor.

The broad applicability of the system is aided by a relatively simple design that can be customized through creation of a short RNA sequence to target a specific sequence in the genome to generate the desired changes. Previous genome editing methods have relied on making custom proteins, which is costly and slow.

"This is so readily transferable that it's highly likely to enable gene knockout and other genome modifications in any organism," including those that have not previously been used for laboratory work, says O'Connor-Giles. "It's going to turn non-model organisms into genetic model organisms."

That ease may also pay off in the clinic. "It can be very difficult and time-consuming to generate models to study all the gene variants associated with human diseases," says Wildonger. "With this genome editing approach, if we work in collaboration with a clinician to find [clinically relevant] mutations, we can rapidly translate these into a fruit fly model to see what's happening at the cellular and molecular level."

The work, led by genetics graduate student Scott Gratz, was the joint effort of three UW-Madison labs -- particularly notable, Harrison says, that each is in a different department and headed by a female assistant professor. "This has been an amazing collaboration," she says. "It wouldn't have worked if any one of us had tried it on our own."

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2013年8月23日星期五

Favorite music makes teens drive badly: Teen driver music preferences increase errors and distractibility

Male novice drivers in particular make more frequent and serious mistakes listening to their preferred music than their less aggressive, female counterparts, the researchers noted.

The BGU study evaluated 85 young novice drivers accompanied by a researcher/driving instructor. Each driver took six challenging 40-minute trips; two with music from their own playlists; two with background music designed to increase driver safety (easy listening, soft rock, light jazz), and two additional trips without any music.

The study was conducted by BGU Director of Music Science Research Warren Brodsky and researcher Zack Slor to assess distraction by measuring driver deficiencies (miscalculation, inaccuracy, aggressiveness, and violations) as well as decreased vehicle performance.

When the teen drivers listened to their preferred music, virtually all (98 percent) demonstrated an average of three deficient driving behaviors in at least one of the trips. Nearly a third of those (32 percent) required a a sudden verbal warning or command for action, and 20 percent needed an assisted steering or braking maneuver to prevent an imminent accident. These errors included speeding, tailgating, careless lane switching, passing vehicles and one-handed driving.

Without listening to any music, 92 percent made errors. However, when driving with an alternative music background designed by Brodsky and Israeli music composer Micha Kisner, deficient driving behaviors decreased by 20 percent.

"Most drivers worldwide prefer to listen to music in a car and those between ages 16 to 30 choose driving to pop, rock, dance, hip-hop and rap," Brodsky explains. "Young drivers also tend to play this highly energetic, fast-paced music very loudly -- approximately 120 to 130 decibels."

"Drivers in general are not aware that as they get drawn-in by a song, they move from an extra-personal space involving driving tasks, to a more personal space of active music listening."

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Business Ballmer to go within a year

2013/08/23

When a $300 billion market cap company sees its shares shoot up 8% something pretty good must have happened to the company.

In Microsoft’s case the pretty good something is the resignation of the CEO – to take effect within the year.

Steve Ballmer presided over the launch of the much-loathed Windows 8, over the move into manufacturing tablets which cost it a $1 billion write-down of unsold stock earlier this month and over the deal with Nokia on hand-sets which has not done much to save the stricken Finnish company.

Making tablets annoyed many of Microsoft’s hardware manufacturing customers, and porting Windows to ARM annoyed Microsoft’s long-time ally Intel.

Ballmer has behaved very oddly in public bouncing around and shouting in his presentations which can be watched on YouTube.

He met Bill Gates at Harvard and became Microsoft’s 30th employee in 1980.

He is worth $15 billion.

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Business Toshiba breaks ground on 3D NAND fab

2013/08/23

Toshiba has started to build its fab for vertical NAND, also called ‘stacked NAND’ or ’3D NAND’.

‘Toshiba will expand Fab 5 to secure manufacturing space for NAND flash memories fabricated with next generation process technology and for 3D memories,’ says the company, ‘construction will be completed in summer next year.’

3D NAND involves stacking memory cells on top of eachother in a similar way to stacked cell DRAM.

NAND market leader Samsung announced earlier this month that it was already producing vertical NAND but it is not thought to be in high volume production.

The third largest NAND producer, Micron, is waiting for 3D NAND to become commercially feasible.

“The key challenge is going to be cost,” says Glen Hawk, vp of NAND Solutions at Micron, “we’re not going to do it until it’s cost-effective – and it needs to be capable of dozens of layers before it’s cost-effective. The debate is about how many hundreds of layers you can stack – nobody knows how many yet.”

Samsung’s first 3D NAND chip, a 128Gbit memory, has 24 layers.

The beauty of stacked NAND is that it removes the need for further scaling. When planar NAND ends, the next generation of NAND – the first generation of 3D vertical NAND – will use a larger geometry process.

“With the vertical NAND stacked cell you can have a more relaxed geometry,” says Hawk, “it’s the first time in my career that we’re selling things that are bigger and cheaper and better all at the same time. Vertical NAND has better reliability and better performance than planar NAND.”

The problem looming for NAND’s future viability was that NAND cells have been running out of electrons as they scale down the micron trail. With a few tens of electrons per cell at sub-20nm, NAND behaviour can become unpredictable. Vertical NAND takes that number back up to hundreds of electrons per cell.

“Vertical NAND is not limited by litho – not limited by fine lines – but by the device physics of the cell,” said Hawk. With quantum effects hitting structures made on 10-20nm processes (where NAND currently is) vertical NAND is the life-saver for NAND technology.

Hawk reckons there will be two more generations of planar NAND and then vertical NAND will come onto the market towards the end of 2015.

“We’re at least two years away from product,” says Hawk, “two years away from it being as cost-effective as planar NAND. When we transition from planar to 3D, the process is very different and the equipment is different – it’s a huge cost.”

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Art preserves skills despite onset of vascular dementia in 'remarkable' case of a Canadian sculptor

The finding, scheduled to be released today in the Canadian Journal of Neurological Sciences, looked at the last few years of the late Mary Hecht, an internationally renowned sculptor, who was able to draw spur-of-the moment and detailed sketches of faces and figures, including from memory, despite an advanced case of vascular dementia.

"Art opens the mind," said Dr. Luis Fornazzari, neurological consultant at St. Michael's Hospital's Memory Clinic and lead author of the paper. "Mary Hecht was a remarkable example of how artistic abilities are preserved in spite of the degeneration of the brain and a loss in the more mundane, day-to-day memory functions."

Hecht, who died in April 2013 at 81, had been diagnosed with vascular dementia and was wheelchair-bound due to previous strokes. Despite her vast knowledge of art and personal talent, she was unable to draw the correct time on a clock, name certain animals or remember any of the words she was asked to recall.

But she quickly sketched an accurate portrait of a research student from the Memory Clinic. And she was able to draw a free-hand sketch of a lying Buddha figurine and reproduce it from memory a few minutes later. To the great delight of St. Michael's doctors, Hecht also drew an accurate sketch of famed cellist Mstislav Rostropovich after she learned of his death earlier that day on the radio.

While she was drawing and showing medical staff her own creations, Hecht spoke eloquently and without hesitation about art.

"This is the most exceptional example of the degree of preservation of artistic skills we've seen in our clinic," said Dr. Corinne Fischer, director at St. Michael's Hospital's Memory Clinic and another of the paper's authors. "As well, most of the other studies that have been done in this area looked at other kinds of dementia such as Alzheimer's disease or frontal temporal dementia, while this is a case of cognitive reserve in a patient with fairly advanced vascular dementia."

Dr. Fornazzari previously wrote a paper detailing a musician who, despite declining health because of Alzheimer's disease, could still play the piano and learn new music. As well, in October 2011, Dr. Fischer and colleagues looked at bilingual patients with Alzheimer's and discovered they had twice as much cognitive reserve as their unilingual counterparts.

Educators should take a page from these results and encourage schools to teach the arts -- whether sculpture, painting or music -- rather than cutting back on them, said Dr. Fornazzari. "Art should be taught to everyone. It's better than many medications and is as important as mathematics or history."

Both physicians want to lead a larger study of artists with neurological illnesses to further explore the importance of art and cognitive brain capacity.

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Fecal microbiota transplantation as effective treatment for C. difficile and other diseases

Aug. 22, 2013 — Fecal microbiota transplantation (FMT) has emerged as a highly effective treatment for recurrent Clostridium difficile (C. difficile) infection, with very early experience suggesting that it may also play a role in treating other gastrointestinal (GI) and non-GI diseases. The topic is examined in the Review Article, "An overview of fecal microbiota transplantation: techniques, indications, and outcomes" in the August issue of GIE: Gastrointestinal Endoscopy.

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Fecal microbiota transplantation refers to the infusion of a suspension of fecal matter from a healthy individual into the GI tract of another person to cure a specific disease. FMT has received public attention recently with the publication of several studies showing that stool is a biologically active, complex mixture of living organisms with great therapeutic potential for Clostridium difficile infection and perhaps other GI and non-GI disorders. C. difficile is a bacterium recognized as the major causative agent of colitis (inflammation of the colon) and diarrhea that may occur following antibiotic intake. The disruption of the normal balance of colonic microbiota as a consequence of antibiotic use or other stresses can result in C. difficile infection. It is now estimated that 500,000 to 3 million cases of C. difficile occur annually in U.S. hospitals and long-term care facilities.

According to authors Lawrence J. Brandt, MD and Olga C. Aroniadis, MD, Montefiore Medical Center, Bronx, New York, current first-line treatment for C. difficile includes cessation of the culprit antibiotic, if possible, and treatment with metronidazole, vancomycin, or fidaxomicin, depending on disease severity. Most patients with C. difficile initially respond to this treatment, but recurrence rates are 15 percent to 35 percent. Patients who have one recurrence have up to a 45 percent chance of a second recurrence, and after a second recurrence, up to 65 percent of patients will have a third. Recurrences are usually treated with additional courses of metronidazole, oral vancomycin, or prolonged oral vancomycin in various pulsed-tapered regimens, occasionally "chased" by other antibiotics such as rifaximin. The high recurrence rates of C. difficile prompted the need for alternative therapies, to which the authors believe FMT offers a rational and relatively simple approach.

The Review Article addresses FMT methodology, including donor and recipient screening, donor selection, how FMT is performed and safety. FMT is most commonly performed via colonoscopy; however, donor feces also have been administered via a nasogastric or nasoenteric tube, gastroduodenoscopy, and enema. All the studies have reported remarkable cure rates without serious adverse effects directly attributable to FMT. The article notes that current literature on FMT for C. difficile predominantly comprises single-center case series and case reports, but also a meta-analysis, two systematic reviews, and one recently published randomized, controlled trial. In all, 92 percent of patients were cured of their recurrent C. difficile, with a range of 81 percent to 100 percent.

In the only long-term follow-up study of FMT to date that included 5-medical centers and 77 patients who had FMT, the patients experienced a 91 percent primary cure rate and an astounding 98 percent secondary cure rate, the latter defined as cure enabled by use of antibiotics to which the patient had not responded before the FMT or by a second FMT. Patients in this study had symptoms for an average of 11 months before FMT, and most (74 percent) reported resolution of diarrhea within three days. FMT also has been successfully used to treat a variety of other GI disorders including inflammatory bowel disease, irritable bowel syndrome, and constipation. There is a growing literature on an altered intestinal microbiome in these and other disorders.

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Cell phones used to measure happiness

In a study involving volunteers who agreed to provide information about their feelings and locations, the researchers found that cell phones can efficiently capture information that is otherwise difficult to record, given today's on-the-go lifestyle. This is important, according to the researchers, because feelings recorded "in the moment" are likely to be more accurate than feelings jotted down after the fact.

To conduct the study, the team created an application for the Android operating system that documented each person's location and periodically sent the question, "How happy are you?"

The investigators invited people to download the app, and over a three-week period, collected information from 270 volunteers in 13 countries who were asked to rate their happiness on a scale of 0 to 5. From the information collected, the researchers created and fine-tuned methods that could lead to a better understanding of how our environments influence emotional well-being. The study was published in the June issue of Demography.

The mobile phone method could help overcome some of the limitations that come with surveys conducted at people's homes, according to the researchers. Census measurements tie people to specific areas -- the census tracts in which they live -- that are usually not the only areas that people actually frequent.

"People spend a significant amount of time outside their census tracks," said John Palmer, a graduate student in the Woodrow Wilson School of Public and International Affairs and the paper's lead author. "If we want to get more precise findings of contextual measurements we need to use techniques like this."

Palmer teamed up with Thomas Espenshade, professor of sociology emeritus, and Frederic Bartumeus, a specialist in movement ecology at the Center for Advanced Studies of Blanes in Spain, along with Princeton's Chang Chung, a statistical programmer and data archivist in the Office of Population Research; Necati Ozgencil, a former Professional Specialist at Princeton; and Kathleen Li, who earned her undergraduate degree in computer science from Princeton in 2010, to design the free, open source application for the Android platform that would record participants' locations at various intervals based on either GPS satellites or cellular tower signals.

Though many of the volunteers lived in the United States, some were in Australia, Canada, China, France, Germany, Israel, Japan, Norway, South Korea, Spain, Sweden and the United Kingdom.

Palmer noted that the team's focus at this stage was not on generalizable conclusions about the link between environment and happiness, but rather on learning more about the mobile phone's capabilities for data collection. "I'd be hesitant to try to extend our substantive findings beyond those people who volunteered." he said.

However, the team did obtain some preliminary results regarding happiness: for example, male subjects tended to describe themselves as less happy when they were further from their homes, whereas females did not demonstrate a particular trend with regards to emotions and distance.

"One of the limitations of the study is that it is not representative of all people," Palmer said. Participants had to have smartphones and be Internet users. It is also possible that people who were happy were more likely to respond to the survey. However, Palmer said, the study demonstrates the potential for mobile phone research to reach groups of people that may be less accessible by paper surveys or interviews.

Palmer's doctoral dissertation will expand on this research, and his adviser Marta Tienda, the Maurice P. During Professor in Demographic Studies, said she was excited to see how it will impact the academic community. "His applied research promises to redefine how social scientists understand intergroup relations on many levels," she said.

This study involved contributions from the Center for Information Technology Policy at Princeton University, with institutional support from the National Institutes of Health Training Grant T32HD07163 and Infrastructure Grant R24HD047879.

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Toxic nanoparticles might be entering human food supply

Aug. 22, 2013 — Over the last few years, the use of nanomaterials for water treatment, food packaging, pesticides, cosmetics and other industries has increased. For example, farmers have used silver nanoparticles as a pesticide because of their capability to suppress the growth of harmful organisms. However, a growing concern is that these particles could pose a potential health risk to humans and the environment. In a new study, researchers at the University of Missouri have developed a reliable method for detecting silver nanoparticles in fresh produce and other food products.

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"More than 1,000 products on the market are nanotechnology-based products," said Mengshi Lin, associate professor of food science in the MU College of Agriculture, Food and Natural Resources. "This is a concern because we do not know the toxicity of the nanoparticles. Our goal is to detect, identify and quantify these nanoparticles in food and food products and study their toxicity as soon as possible."

Lin and his colleagues, including MU scientists Azlin Mustapha and Bongkosh Vardhanabhuti, studied the residue and penetration of silver nanoparticles on pear skin. First, the scientists immersed the pears in a silver nanoparticle solution similar to pesticide application. The pears were then washed and rinsed repeatedly. Results showed that four days after the treatment and rinsing, silver nanoparticles were still attached to the skin, and the smaller particles were able to penetrate the skin and reach the pear pulp.

"The penetration of silver nanoparticles is dangerous to consumers because they have the ability to relocate in the human body after digestion," Lin said. "Therefore, smaller nanoparticles may be more harmful to consumers than larger counterparts."

When ingested, nanoparticles pass into the blood and lymph system, circulate through the body and reach potentially sensitive sites such as the spleen, brain, liver and heart.

The growing trend to use other types of nanoparticles has revolutionized the food industry by enhancing flavors, improving supplement delivery, keeping food fresh longer and brightening the colors of food. However, researchers worry that the use of silver nanoparticles could harm the human body.

"This study provides a promising approach for detecting the contamination of silver nanoparticles in food crops or other agricultural products," Lin said.

Members of Lin's research team also included Zhong Zang, a food science graduate student. The study was published in the Journal of Agricultural and Food Chemistry.

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Sticking power of plant polyphenols used in new coatings

And so can red wine, dark chocolate and cacao beans, they found. It's the powerful and healthful polyphenols at work in a new way. (Polyphenols are naturally occurring molecules found in plants whose functions include structural support and defense against bacteria and oxidative damage.)

Polyphenols are sticky, and the researchers exploited this useful property, while also retaining some of the compounds' well-known biological properties. They made new multifunctional coatings based on tannic acid and pyrogallol -- inexpensive compounds resembling the more complex polyphenols found in tea, wine and chocolate.

Simply dissolving polyphenol powder in water with the proper dash of salt quickly produces colorless coatings that have antioxidant properties, are non-toxic and can kill bacteria on contact.

The coatings -- which can stick to virtually anything, including Teflon -- could be used on a wide range of consumer, industrial and medical products, from catheters and orthopedic implants to membranes for water purification and materials used in food processing, packaging and preparation.

The study is published today (Aug. 22) in the journal Angewandte Chemie.

"We discovered a way to apply coatings onto a variety of surfaces that takes advantage of the sticky properties of the polyphenol compounds," said Phillip B. Messersmith, who led the research. "It's a very simple dip-coating process, and the antibacterial and antioxidant properties are preserved in the coating."

One could take a stainless-steel hip implant, he said, apply the process to it, and the coating that emerges spontaneously and with no other modifications will kill bacteria and quench reactive oxygen species, such as free radicals.

Messersmith is the Erastus O. Haven Professor of Biomedical Engineering at Northwestern's McCormick School of Engineering and Applied Science.

Messersmith's team tested all kinds of materials -- medically relevant polymers, engineering polymers, metals, inorganic substrates and ceramics -- and a coating stuck to each one. The researchers also demonstrated they can easily modify the coatings to give them additional functions, such as an antifouling property to prevent cells from building up on a surface, such as a pacemaker.

"What's interesting is that the raw materials we regularly encounter in our diets can benefit us in a way we had never envisioned -- as coatings on medical devices," said Tadas S. Sileika, a graduate student in Messersmith's lab and first author of the paper.

"The coatings innately have properties that are very beneficial to saving lives and keeping people healthy. Without any further modification, they can help prolong the life of a medical device, reduce inflammation in a patient and prevent bacterial infections," he said.

For 15 years, Messersmith's lab has been developing new biomedical materials, including another coating called polydopamine, also based on phenols, which are found in the sticky glue that marine mussels use to stick to rocks. Because of their chemical similarities, Messersmith and his colleagues wondered if the phenol compounds found in plant-derived red wine, green tea and dark chocolate might have similar sticking power.

This curiosity led to the kitchen sink experiments in which the researchers detected a colorless residue left behind on containers exposed to green tea and red wine. Experiments using polyphenol-rich food extracts from green tea, red wine, dark chocolate and cacao beans also produced coatings.

Messersmith and his team then went one step farther: after finding this behavior also holds for low-cost polyphenols and similar compounds, they developed a simple method for producing the multifunctional coatings.

They found that immersing objects into a saline solution of tannic acid or pyrogallol results in spontaneous coating deposition, just like what happened with the extracts and beverages. Using these inexpensive precursors instead of the extracts improves the speed and lowers the cost of the process, increasing its commercial viability, the researchers said.

"The stickiness of plant polyphenols is behind the so-called astringency effect that people can experience when drinking red wine high in tannins," Messersmith said. "The tannins stick to, or bind, saliva proteins, producing the sensation of puckering and dryness. We've put this stickiness to work in a novel way."

Polydopamine has shown great promise as a biomedical coating, but the plant polyphenol-based coatings can trump it in two important ways: The plant polyphenol-based coatings are colorless, so they don't alter a material's optical properties, and the compounds used to produce them are roughly 100 times cheaper. And that's in addition to their innate antibacterial and antioxidant properties.

The coatings also are only between 20 and 100 nanometers thick, depending on the material being coated, so would not alter biomedical instruments in a negative way.

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Why people with red hair have a higher risk of developing melanoma

Aug. 22, 2013 — A person's skin pigment, which determines hair color and skin tone, is influenced by the melanocortin-1 (MC1R) gene receptor. For the population's one to two percent of redheads, a mutation in MC1R accounts for their red hair color and typical light skin.

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Now researchers from Beth Israel Deaconess Medical Center (BIDMC) and Boston University School of Medicine (BUSM) have discovered that the same MC1R mutation responsible for the red hair phenotype also promotes an important cancer-causing pathway. The new findings, reported online today in the journal Molecular Cell, help to explain the molecular mechanisms that underlie redheads' well-known risk of developing melanoma, providing new insights for treating and preventing this dangerous type of skin cancer.

Melanoma is the least common but the most lethal of skin cancers. Accounting for 75 percent of all skin-cancer deaths, melanoma originates in pigment-producing skin cells called melanocytes. Melanoma is believed to be a multi-step process (melanomagenesis) of genetic mutations that increase cell proliferation, cell differentiation and cell death and increase an individual's susceptibility to ultraviolet (UV) radiation. Two types of UV radiation -- UVA and UVB -- can mutate DNA in skin cells and lead to melanoma.

"In this current study, we have demonstrated that the mutation MC1R-RHC promotes the PI3K/Akt signaling pathway when a red-haired individual is exposed to UV radiation," explains co-senior author Wenyi Wei, PhD, an investigator in the Department of Pathology at BIDMC and Associate Professor of Pathology at Harvard Medical School. PI3K/Akt is a well-known cancer-causing pathway, implicated in breast cancer, ovarian cancer and lung cancer.

Previous work by the study's co-senior author Rutao Cui, MD, PhD, a member of the BUSM Department of Dermatology, had demonstrated that MC1R plays a key role in protecting melanocytes from UV-induced DNA damage. In this current study, Wei and Cui wanted to find out how this was happening.

Led by co-first authors, Lixin Wan, PhD, a member of the Wei laboratory at BIDMC and Juxiang Cao, PhD, a member of the Cui lab at BUSM, the scientific team embarked on a series of experiments in both cell cultures and mouse models. Their experiments showed that in normal circumstances, MC1R was binding to PTEN, a well-known tumor suppressor gene. PTEN acts to safeguard against cancer; without PTEN, the end result is elevated signaling in the cancer-causing P13K/Akt pathway.

The team then went on to demonstrate that MC1R-RHC mutations found in red-haired individuals lacked this protective mechanism. "As a result, upon UVB exposure, we saw an increased destruction of PTEN in the mutated pigment cells," says Wei. The team additionally found that in these same MC1R-RHC pigment cells, elevated PI3K/Akt activity was boosting cell proliferation and was synchronizing with another well-known cancer mutation in the BRAF gene (found in nearly 70 percent of human melanomas) to further accelerate cancer development. In support of these results, note Wei and Cui, another research group at Massachusetts General Hospital recently demonstrated that expression of the BRAF gene mutation in the melanocytes of mice carrying a mutated MC1R gene led to a high incidence of invasive melanomas.

"Together, our findings provide a possible molecular mechanism as to why red-haired individuals harboring MC1R mutations are much more susceptible to UV-induced skin damage than individuals with darker skin, resulting in a 10-to100-fold higher frequency of melanoma," says Wei.

The authors note that this newly established link between MC1R and PTEN will be a starting point for future studies, adding that it remains unclear why only MC1R genetic variants linked to the red hair phenotype -- but not all MC1R variants -- are unable to bind to PTEN following UV exposure.

"We think that MC1R variants, in combination with mutations in the BRAF gene, could be used as markers of an increased risk of developing melanoma," explains Wei. The authors add that these new findings suggest that drug inhibitors that target the PI3K/Akt signaling pathway might be used in combination with Vemurafenib, a drug that targets the BRAF oncogenic protein, to treat melanoma patients who have both BRAF and MCIR variants.

Study coauthors include Xiangpeng Dai of BIDMC; BUSM investigators Byungwoo Ryu, Rhoda M. Alani and Stefania Lenna; Elke Hacker of the Queensland (Australia) University of Technology; Celia Jimenez-Cervantes of the University of Murcia, Spain; Yongjun Wang of the Longhua Hospital, Shanghai, China; Nick R. Leslie of Heriot Watt University, Edinburgh, UK; George X. Xu of the University of Pennsylvania; Hans R. Widlund of Brigham and Women's Hospital; Ken Dutton-Regester and Nicholas Hayward of Queensland (Australia) Institute of Medical Research; and Colin R. Goding of the University of Oxford, UK.

This work was supported by grants from the National Institutes of Health (1RO1CA137098; UL1-TR000157; GM089763), the American Cancer Society, the Harry J. Lloyd Charitable Trust, the National Health and Medical Research Council of Australia; the National Basic Research Program of China; the Key Program of Natural Science Foundation of China; and the Program for Changjiang Scholars and Innovative Research Team in University.

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